Inhibition of the lipid kinase PI3Kδ is a promising principle to treat B and T cell driven inflammatory diseases. Using a scaffold deconstruction−reconstruction strategy, we identified 4-aryl quinazolines that were optimized into potent PI3Kδ isoform selective analogues with good pharmacokinetic properties. With compound 11, we illustrate that biochemical PI3Kδ inhibition translates into modulation of isoform-dependent immune cell function (human, rat, and mouse). After oral administration of compound 11 to rats, proximal PD markers are inhibited, and dose-dependent efficacy in a mechanistic plaque forming cell assay could be demonstrated.
If ammonia is used as amine component in Ugi reactions, the desired peptide sometimes is obtained only as the minor product or in traces. Side reactions such as six-component couplings are responsible for this observation. These side reactions can be suppressed by using non-nucleophilic alcohols, such as trifluoroethanol, sterically demanding aldehydes and carboxylic acids.Non proteinogenic amino acids are found in a wide range of peptides and cyclopeptides produced by marine organisms and microorganisms. 1 Many of these structures, especially the cyclic peptides, are highly interesting from a pharmaceutical point of view. 2 Unfortunately, the quantities isolated from natural resources are often very small, and therefore for therapeutic applications and/or for structure/activity investigations efficient synthetic concepts are necessary to provide enough material. Especially for the later point, the improvement of the biological activity of a lead structure, peptide modifications in a side chain 3 or on the backbone 4 are very efficient tools. In addition, multicomponent reactions such as the Ugi reaction allow a straightforward approach towards peptide fragments containing unnatural amino acids. 5 In most cases good results are obtained with primary amines, giving rise to a wide range of N-alkylated peptides. In contrast, only a few examples are described where ammonia was used as a nitrogen source. 6 This is quite surprising, because the 'more natural' NH amide bonds are formed in this case. But in general the yields obtained with ammonia are significantly lower, compared to other amines, and in addition, the new formed stereogenic center is obtained in racemic form. Therefore several attempts have been undertaken to solve these problems by using chiral primary amines, especially those, which can be cleaved after the reaction providing the unsubstituted NH bond. First investigations were carried out with chiral b-alanine derivatives, 7 phenylethylamine 8 and a-ferrocenylalkylamines. 9 Meanwhile, best results are obtained with amines derived from carbohydrates, where the amino functionality is located at the anomeric position. 10 These auxiliaries can be cleaved under acidic conditions. The same approach can also be applied to solid phase synthesis of peptides. 11Recently, we reported a straightforward approach towards the synthesis of cyclic peptides using the Ugi reaction in combination with a ring closing metathesis (RCM). 12 As described by Grubbs and others, RCM is a very powerful tool for the synthesis of cyclic peptide structures. 13During these investigations we became interested in Ugi reactions with ammonia, because from a combinatorial point of view, the formation of diastereomers in similar amounts is convenient and the stereoisomeric cyclopeptides can easily be separated by chromatography. As a model reaction we investigated the reaction of isobutyraldehyde with the isonitrile obtained from glycine methylester and the ammonium salt of various carboxylic acids in methanol. No product was obtained with...
A simple approach to several cyclopeptidmimetics containing an N-alkylated amino acid was found via a multicomponent reaction followed by a ring-closing metathesis starting from readily available precursors. The combinatorial technique has the advantage that different polar, hydrophilic or hydrophobic moieties can be placed at any position in the cycles and unnatural amino acids can also be incorporated.
Chelated enolates are versatile nucleophiles for palladium-catalysed allylic alkylations. Even with complex allylic substrates the reaction proceed without significant isomerisation. This allows the stereoselective introduction of polyhydroxylated allylic sidechains into amino acids and peptides with retention of the olefin geometry.
If ammonia is used as amine component in Ugi reactions, the desired peptide sometimes is obtained only as the minor product or in traces. Side reactions such as six-component couplings are responsible for this observation. These side reactions can be suppressed or favoured depending on the reaction conditions used.Non-proteinogenic amino acids are found in a wide range of peptides and cyclopeptides produced by marine organisms and microorganisms. 1 Many of these structures, especially the cyclic peptides, are highly interesting from a pharmaceutical point of view. 2 Unfortunately, the quantities isolated from natural resources are often very small, and therefore for therapeutic applications and/or for structure-activity investigations efficient synthetic concepts are necessary to provide enough material. Multicomponent reactions such as the Ugi reaction allow a straightforward approach towards peptide fragments containing unnatural amino acids. 3 In most cases good results are obtained with primary amines, giving rise to a wide range of N-alkylated peptides. In contrast, only a few examples are described where ammonia was used as a nitrogen source. 4 This is quite surprising, because the 'more natural' NH amide bonds are formed in this case. But in general the yields obtained with ammonia are significantly lower, compared to other amines.Recently, we reported a straightforward approach towards the synthesis of cyclic peptides using the Ugi reaction in combination with a ring-closing metathesis (RCM). 5 As described by Grubbs and others, RCM is a very powerful tool for the synthesis of cyclic peptide structures. 6During these investigations we became interested in Ugi reactions with ammonia, and as a model reaction we investigated the reaction of isobutyraldehyde with the isonitrile obtained from glycine esters and the ammonium salt of various carboxylic acids in methanol. 7 No product was obtained with salts of strong acids such as trifluoroacetic acid, toluenesulfonic acid or pentafluorobenzoic acid, while benzoic acid gave the expected peptide 1, albeit in moderate yield. Two major side products were formed depending on the reaction conditions (Scheme 1). When ammonium benzoate was treated with isobutyraldehyde (R = i-Pr) and the isonitrile in a 1:1:1 ratio, peptide 1 was obtained only in traces (5%) while the major product was 2, which was isolated in 33% yield. Obviously a six-component coupling is more favoured under these conditions than the Ugi four-component reaction. To suppress this undesired side reaction we decided to use a less nucleophilic solvent. Indeed, in trifluoroethanol no such side product was observed, and the required Ugi product was obtained in 45% yield. Scheme 1 Ugi reactions with ammonium saltsA similar effect was observed during replacing the isobutyraldehyde by the sterically more demanding pivaldehyde. In this case, the desired Ugi product could be obtained in excellent yield. Even in methanol as solvent the yield was higher than 50%. 7 Similar observations were described previously ...
PeptidesPeptides U 0400 Via Ugi Reactions to Conformationally Fixed Cyclic Peptides. -A novel approach to several cyclopeptidmimetics (VI) containing an N-alkylated amino acid is found via a multi-component Ugi reaction followed by a ring-closure metathesis. -(HEBACH, C.; KAZMAIER, U.; Chem. Commun. (Cambridge) 2003, 5, 596-597; Inst. Org. Chem., Univ. des Saarlandes, D-66123 Saarbruecken, Germany; Eng.) -M. Paetzel 25-193
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